The insulin-like growth factor 1 (IGF1) pathway plays an important role in regulating aging and longevity. Single gene mutations in the IGF1 pathway extend longevity in a variety of organisms, including yeast, worms, flies and rodents. Epidemiological studies found that lower IGF1 signaling is associated with longer longevity. In the normal human population, IGF1 levels vary dramatically and genetic polymorphisms play an important role in determining IGF1 levels. However, the mechanisms that allow genetic polymorphisms to regulate IGF1 levels have not been revealed. Furthermore, our studies suggest that IGF1 is regulated by a complex network of genetic loci containing previously unrecognized genes. We propose to study IGF1 gene regulation using an innovative, unbiased approach that combines critical mouse resources with traditional QTL analysis and newly developed bioinformatics methods to identify candidate genes. Our method includes: 1) Determining the genetic loci that determine IGF1 levels in an intercross population, 2) Identifying candidate genes that regulate Igf1, excluding the Igf1 locus itself, using combined cross and haplotype analyses, and 3) Narrowing the list of candidate genes using gene sequencing and expression data. The IGF1 regulating genes identified in this study will provide insights into key genetic mechanisms regulating aging and longevity, as well as age-related disorders, such as cancer and heart disease. As the mouse is an excellent model for understanding the genetic regulation of human biological and pathological traits, the data will allow candidate gene analysis and association studies in the human population. ) PUBLIC HEALTH RELEVANCE: Insulin-like growth factor 1 (IGF1) is a vital hormone that regulates human aging. Differences in IGF1 levels are associated with changes in longevity and disease and have been linked with differences in individuals'genetic codes. Using mouse models, our studies will identify these genetic variations and examine their role in controlling IGF1 and aging. Ultimately, our work will reveal factors that regulate the human aging process and identify treatments for age related diseases, such as cardiovascular disease and cancer.